I

Dr. Mohd Azharuddin

CONTROLLED DRUG DELIVERY SYSTEM

INTRODUCTION:

• Drugs can be administered through various routes; however, of all the routes of
administration, oral route of admini~tration is the most convenient for administering
and for dosage adjustments.

• Important reason for their popularity is their convenience of application and the ease
of preparation on an industrial scaie

• Coi1trolled drug delivery occurs when a polymer is combined with a drug or active
ageht such that the release from tbe bulk material is .pre-designed.

• Controlled and Sustained Release, both has been used in consistent and confusing
manner. Both represent separate delivery process.

• Sustained release system generally don't attain zero order type release and usually try
to mimic zero order release by providing drug in a slow first order

~ e basic rationale for controlled drug delivery is to alter the pharmacokinetics and
,fJi5P
pharmacodynamics of pharmacologically active moieties by using novel drug·delivery
system or by modifying the molecular structure and /or physiological parameters
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Drug levels in blood

TVM College of Pharmacy Page 1

.I
 Dr. Mohd Azharuddin
=--
DEFINITION:

• Qelivery of the drug at predetennined rate or to a location according to the need ofth1;;
body disease state for a definite time period.

ADVANTAGES:

• Decreased fluctuation in circulating drug levels--resulting in reduced toxicity and

sustained efficacy.

• Decreased frequency of dosing.

• Increased patient compliance.

• Avoidance ofnight time dosing.

• Reduced patient care time

DISADVANTAGES:

• Longer time to achieve therapeutic blood concentrations.

•
Increased variation in bioavailability.

Dose-dumping - Toxicity

Sustained concentration in overdose cases.

I
• Lack of dosage flexibility.

• Greater expense.

• Need for additional patient education & counselling.

SELECTION OF DRUG CANDIDATES:

• The release of the drug depends upon the formulation & physicochemical properties
of the drug while movement of the drug depends upon pharmacokinetics of drug.

Drug in the Release Drug at the Absorption. Drug in the

dosage form absorption site body

1
Rate limiting step
l
Rate limiting step
of CODS of conventional
dosage forms .

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TVM College of Pharmacy
 Dr. Mohd Azharuddin
Characteristics of Drugs Not Suitable for
the Controlled Release Dosage Forms:
• Very Short Or Long Half Life

• Narrow Therapeutic Index

• Poor Absorption

• Large Doses

• Low Aqueous Solubility

• Extensive First Pass Metabo \ism

APPROACHES FOR DESIGNING OF CDD

S: \_)0 ~1
• Diffusion

• Dissolution

• Ion-exchange

Diffusion CDDS
• Basically diffusion process shows the mov
ement of drug molecules from a region qf a
higher concentration to one of lower concentra
tion.
• The flux of the drug J (in amount/ area -time
), across a membrane in the direction of
decreasing concentration is given by Fick's
law.
J.= -Ddc/dx
Where, D = diffusion coefficient in area/time

dc/dx = change of concentration 'c' with dista

nce 'x'
• Diffusion systems are characterized by relea
se rate of drug is dependent on its
diffusion through inert water insoluble mem
brane barrier.
• Tilere are basically two types of diffusion devi
ces.
1. Reservoir-Type

2. Matrix Type

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 Dr. Mohd Azharuddin

1. Reservoir Type

• lfl the system, a water insoluble polymeric material encloses a core of drug, which
controls release rate.
• Drug will partition into the membrane and exchange with the fluid surrounding the
particle or tablet.

• Additional drug will enter the polymer, diffuse to the periphery and exchange with the
surrounding media The polymers commonly used in such devices are ethyl cellulose
and poly-vinyl acetate.

time• 0

The rate of drug released (dm/dt) can be calculated using the following equation

dm/dt = (ADK) !::.Cl t

Where, A= Area, D = Diffusion coefficient,

K = Partition coefficient of the drug between the drug core and the membrane,

e= Diffusion path length and l::iC = Concentration difference across the membrane.
Advantage:

• By this syst~m Zero order delivery is possible, release rates variable with polymer
type.
Disadvantages:

• System must be physically removed from implant sites.

• Difficult to deliver high molecular weight compound, generally increased cost per
dosage unit, potential toxicity if system fails

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 Dr. Mohd Az har udd in
2. Matrix Type

A so lid drug is homogenously disp

ersed in an insoluble matrix and the
of dtug is dependent on the rate rate of release
of drug diffusion and not on the
dissolution. rate of solid

poly111cr

time · O tim e - t

Advantages:

Easier to produce than reservoir or

encapsulated devices, can deliver high
weight .compounds. molecular

Disadvantages: ·

Cannot provide zero order release,

removal of remaining matrix is nec
implanted system. essary for

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V
I
Dr. Mohd Azharuddin

CONTROLLED DRUG DELIVERY SYSTEM

Dissolution CDDS

• Drugs having high aqueous so\ubi\ity and dissolution rate, shows

challenge in
contro\\ing their disso\ution rate.

• Disso\ution-contro\led re\ease can be obtained by slowing the dissolu

tion rate of a
drug in the G\ medium, incorporating the drug in an insoluble polyme
r and coating
drug partic\es or granules with polymeric materials of varying thickness.

• Th~ rate limiting step for dissolution of a drug is the diffusion across
the , aqueous
boundary layer.

• The solubility of the drug provides the source of energy for drug
release, which is
countered by the stagnant-fluid diffusional boundary layer.

• -The rate of dissolution (dm/dt) can be approximated by

dm/dt = ADS/h
Where, S = Aqueous solubility of the drug.

A= Surface area of the dissolving particle or tablet.

D = Diffusivity of the drug and

h = Thickness of the boundary layer.

There are basically two types of dissolution devices.

I. Encapsulation Dissolution Controlled Systems

2. Matrix Dissolution Controlled Systems

1. Encapsulation Dissolution Controlled Systems

• The drug particles are coated or encapsulated by microencapsulation techniq

ues with
slowly dissolving materials like cellulose, poly ethylene glycols, polyme
thacrylates,
waxes etc.
• The dissolution rate of coat depends upon the solubility and thickness of
the coating.
• Those with the thinnest layers will provide the initial dose.

• The maintenance of drug levds at late times will be achieved from those
with thicker
coating.

TVM College of Pharmacy Page 1

 Dr. Mohd Azharuddin
~
~ Olaaofvlng coat

~"'"•'"~·
Qrug

B
© t /
0
Varied ThJckn••• of
Dl••olv1ng Coat

,
Encapsulation Dissolution Controlled Systems

2. Matrix Dissolution Controlled Systems

• _ln matrix systems the drug is homogeneously dispersed throughout a rate controlling
.
I
medium.

They employ waxes such as beeswax, camauba wax, hydrogenated castor oil etc
which control drug dissolution by controlling the rate of dissolution fluid penetration
into the matrix by altering the porosity of tablet, decreasing its wettability or by itself
getting dissolved at a slower rate.

The drug release is often first order from such matrices.

The wax embedded drug is generally prepared by dispersing the drug in molten wax
and solidifying and granulating the same.
Tlme•O Tlme. •t
x X :r. Releoaed druga
l. :r. ,., l (dlaaolved)
X • >< l
2.
>< x .i,· it- - Eroded polym•r
:<...,,
1 >< ,e r. '
>< l Pore& formed by
Drug& dlaperaed In dlaaolutlon and
polymer matrix Undegraded diffusion of drug
polymer matrix aggregates -~

Matrix Dissolution Controlled Systems

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I
/ Dr. Mohd Azharuddin

\on-exchange CDDS

• Resins are water-insoluble materials containing anionic or cationic groups in

repeating positions on the resin chain.

• The drug-charged resin is prepared by mixing the resin with drug solution either by
repeated exposure of the resin to the drugs in a chromatographic column or by
keeping the resin in contact with the drug solution for extended period of time.

• The drug-resin is than washed to remove contaminant ions and dried to form particles
or bead.

• Wl-ien a high concentration of an appropriately charged ion is in contact with' the ion-
exchange group, the drug molecules is exchanged and diffuses out of the resin to the
bulk solution.

Cationic drugs:

• The cationic drugs forms a complex with anionic ion exchange resin
• Ex: A resin with so3· (Sulfite)

• In the GIT hydronium ion (W) in the GIT fluid penetrates the system and activate the
release of cationic drug from drug-resin complex. ·
Drug+ - Resin - S03· + W (ion) ---+ W - Resin - So 3· +Drug +
Anionic drugs:

• The anionic drugs forms a complex with cationic ion exchange resin

• Ex: A resin with [N (CH3t] (Trimethylamine)

• In the GIT chloride ion (Cl") in the GIT fluid penetrates the system and activate the
1

release of anionic drug from drug-resin complex.

Drug· - Resin - [N (CH3t] + c1- (ion) ---+ c1- - Resin - [N (CH 3r] + Drug -

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I

Fnctors ntll•cting the Formulntion

of Ornl CODS
• The re are two mu jor fuc tors tha
t affe ct the rele ase rate from
the CDDS. The y are :
I. Phy sico che mic nl fuctors

2. Bio log ical factors.

l. Physicochemical Properties
of Drug
a) Aqu eou s solu bili ty

b) Partition coe ffic ien t (P (0/ W]

r )
c) Dru g pKn and ion izat ion at
phy siol ogi cal pH
d) Dru g stability

e) Mo lecu lar wei ght and diff

usiv ity
t) Pro tein bin din g

g) Dos e size.

a) Aq ueo us solubility

• Mo st of the dru gs are wea k acid

s or wea k bases.
• Drugs wit h low water solubility
will be difficul t to inc orp ora te into CR mec han
ism .
• For a dru g with high solubility
and rapid dissolution rate, it is
retard its dissolution rate . ofte n qui te diff icu lt to

• A drug of high water solubility

can dissolve in wat er or GI flui
release its dosage form in a bur d rea dily and ten ds to
st and thu s is absorbed qui ckl
i~crease in the blood dru g concen y leading to a sha rp
tration compared to less soluble
drug.
• It is often difficult to incorporate
a highly water-soluble dru g in
retard the dru g release, especially the dos age form a nd
when the dose is high.
• The pH-dependent solubility,
particularly in the physiological
another problem for CR formulat pH range~ would be
ion because of the variation in
GI tract and variation in the diss the pH thro ugh out the
olution rate.
• The biopharmaceutical classifi
cation system allows estimat
contribution of three major fact ion of the like ly
ors which affect the oral absorp
tion .
• Solubility

• Dissolution and

Inte stinal permeability.

TVM College of Ph arm acy

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 Dr. Mohd Azharuddin

• C\ass \\\ (h,gh so\ubifay.\ow permeability) and Class IV (low solubility-low

~enneab\\ity) drugs are poor candidates for CR dosage form compound with
so\ub\\ity so\ubi\isatlon obstacles and often compounds with solubility 10 mg/ml
~resent difflcu\t\es to so\ubi\isation dosing formulation.

~enera\, high\y so\ub\e drugs are undesirable for formulation into an CR product.

bf?art\tion coeffldent (I> lO/W\)

• The -partition coetTtcient is defined as the fraction of drug in an oil phase to that of an
ad1acent aqueous µhase.

Partit\on coefficient influences not only the permeation of the drug across the
bio\ogica\ membranes but also diffusion across the rate controlling membrane or
matrix between the time when a crug is administered, and when it is eliminated from
the body, it must diffuse through a variety of biological membranes that act primarily
as \iµid-\ike barriers.

• Major criterion in evaluation of the ability of a drug to penetrate these lipid

membranes (i.e., its membrane permeability) in its apparent oil or water partition
coefficient defined as,

K= Co/Cw

• Where, Co= Equilibrium concentration of all forms of the drug in an organic phase at
equilibrium, Cw= Equilibrium concentration of all forms in an aqueous phase.

? I n general, drugs with an extremely large value of K are very oil soluble and will
~ partition into membranes quite readily.

c) Drug pKa and ionization at p_h.µ[Link]-l!!!.....

--:-
• Drugs existing largely in an ionized form are e._oor candjdat~s for oral CR DDS.

• Absorption of the unionized drugs is well whereas permeation of ioni!ed drug is

negligible because the absorption rate ~f the ionized drug is 3-4 times less than that of
the unionized drug.
• The pKa range for an acidic drug whose ionization is pH sensitive is around 3.0-7.5
and pKa range for a basic drug whose ionization is pH sensitive is around 7.0-11.0 are
ideal for optimum positive absorption. 5

• · Drug shall be unionized at the site to an extent 0.1-5.0%

d) Drug stability
• Drugs undergo both acid/base hydrolysis and enzymatic degradation when
administered oral route.

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1VM College of Pharmacy
 //qrugs that are unstable in gastric [Link]...can be developed as slow release dosage form
d and drug release can be delayed until the dosage form reaches the intestine.--,,__

- ~[Link] undergo gut wall metabolism and show instability in the small intestine are
:::f" ~ot suitable for CR system.

In such case. the drug can be modified chemically to form prodrugs, which may
possess different physicochemical properties or a different route of administration
should be chosen.

e) Molecular weight and diffusivity

:
Diffusivity is defined as the ability of a drug to diffuse through the membrane.

• Diffusivity depends on size and shape of the cavities of the membrane .

The diffusion co-efficient of intermediate drug molecular weight is 100-400 Daltons;

through flexible polymer range is JO---<i ... 10-- 9 cm 2/seconds.

Molecular size or weight is indirectly proportional to the infusibility.

Drugs with larger mo lecu tar size are a poor candid ate for oral -CR system

t) Protein binding

• It is well-known that many drugs bind to plasma proteins with concomitant influence
on the duration of drug action.

r i n c e blood proteins are four the most part re-circulated and not eliminated, drug
protein binding can serve as the depot for drug producing a prolonged release profile,
especially if a high degree of drug binding occurs.

~ h e drug interaction and the period of binding with mucin-like protein also influence
1/ the rate and extent of oral absorption.
g) Dose size

• For orally administered systems, there is an upper limit to the bulk size of the dose to
be administered.

• In general, a single dose of0.5--1.0 g is considered maximal for a conventional dosage

form .

• This also holds for controlled-release dosage forms. f

• Those compounds that require large dosing size can sometimes be given in muhiple
amounts or formulated into liquid system.

~nother consideration is the margin of safety involved in the administration of large

Y amounts of a drug with narrow therapeutic range .

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 Dr. Mohd Azharuddin

CONTROLLED DRUG DELIVERY SYSTEM

2. Biological factors.

a) Absorption

b) Distribution

c) Metabolism

d) Biological half-life/duration of action

-e) Matgin of safety/therapeutic index

·t) Side effect

g) Disease state.

a) Absorption

• - The constant blood or tissue concentration of drug can

be obtained from the oral CR
systems through uniform and consistent release as well as
absorption of the drug.
• The desirable quality of the sustaining system is that
it should release completely
absorbed.

• Apparently the release of the drug from the system is the

rate limiting step, where
rapid absorption relative to the_drug release is always expec
ted, i.e., Kr << Ka.
• lf we assume the transit time of dosage fonns in the absorp
tive areas of GI tract is
about 8-12 hrs, the maximum half-life for absorption should
be approximately 3-4 hrs.
• Otherwise, the dosage form will pass out of absorptive region
s before drug release is
complete.

• Therefore, the compounds with lower absorption rate consta

nts are poor candidates.
• Some possible reasons for the low ~xtent of absorption
are poor water solubility,
small partition co-efficient, protein binding, acid hydrolysis
and metabolism or site
specific or dose-dependent absorption.'

• Drugs with the high apparent volume of distribution,

·1
which influence the rate of
elimination of the drugs, are a poor candidate for oral CR DDS.
• A drug which extensively metabolizes is not suitable for CR
DDS.
• A drug capable of inducing metabolism, inhibiting metab • at
olism, metabolized the
site of absorption or first-pass effect is the poor candidate
for CR delivery, as it could
be difficult to maintain constant blood level.

TVM College of Pharmacy Page 1

 Dr. Mo hd Azh aru ddi n

n. eithe r in the lume n or the tissu es of the

• Drug s that are meta boli zed befo re abso rptio
y from the cont rol relea sing syst ems.
intes tine. can show decr ease d bioa vaila bilit

b) Dist ribu tion

r
the tissu e and cells can be the prim ary facto
• The distr ibut ion of drug mole cule s into
in part icula rly drug elim inati on kine tics.
of circu latin g drug , but it also can be rate
• Sinc e it not only lowe rs the conc entra tion
extra vasc ular tissue.
limi ting in its equi libri um with bloo d and
e drug to the tissu es and bloo d prot eins.
• 'Fhe distr ibuti on inclu des the bind ing ofth
idere d as inac tive and unab le to perm eate
• Prot ein- boun d drug s mole cule s are cons d
ee of prot ein bind ing prov ides prol onge
biolo gica l mem bran es, and a high degr
ther apeu tic actio n

• The appa rent volu me of distr ibuti on is one

.
of the impo rtant para mete rs of the drug
.
s
as well as prot ein bind ing with in the body
that desc ribe the mag nitud e of distr ibuti on
ma
the prop ortio nalit y cons tant of the plas
• The appa rent volu me of distr ibuti on is
amo unt in the body.
conc entra tion of the drug to the total drug

/{' ~ hus for the desi gn of cont rol relea se prod

disp ositi on of drug .
ucts, one mus t have info rmat ion of the

J /
Met abol ism

Meta bolis m of the drug is eithe r an i~ac tivat

-- ·
ion of an a c ~ g or conv ersio n of an
inac tive drug to an activ e meta bolit e. ·
e
ty of tissu es, whic h are cont ainin g mor
Meta bolis m of the drug occu rs in a varie
/· / nzym es.
or
befo re abso rptio n, eithe r in the lume n
/4 Drug s that are sign ifica ntly meta boliz ed er-re leas ing
d bioa vaila bilit y from slow
tissue of the intestine, can show decr ease
dosa ge forms.
. •
/ rytost intes tinal wall enzy me syst ems are satu rable
to
thes e regio ns, less total drug is pres ente d
/ As the drug is relea sed at a s lowe r rate to ersio n of
d, a llow ing mor e com plet e conv
the enzy mati c proc ess duri ng a spec ific perio
the drug to its meta bolit es .
•
eptib le com poun ds as prod rugs is anot her
/ The form ulati on of thes e enzy mati cally susc
viab le solu tion .

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1VM College of Pha rma cy
 Dr. Mohd Azharuddin

/4ugs that are capable of either inducing or inhibiting enzyme synthesis. they are the
,.......-
I
~ ~oor candidate for CR delivery system due to difficulty in maintaining uniform blood
levels. ·

#rugs possessing variation in bioavailability due to the first-pass effect or intestinal

/ metabolism are not suitable for CR DDS

riological half-life/du ration of action

• The usual goal of an oral sustained-release product is to maintain therapeutic blood

~eriod.

~ i o n significant! , influences the desiun of oral CR delivery system

~ ani 11s ependent on the biological half-life.
• Factors influencing the biological half-life of a drug include its elimination.
metabolism and distribution patterns.

rugs with short half-lives required frequent dosing to minimize fluctuations in the
blood levels.

~ CR dosage forms would appear very desirable for such drugs.

• For a given steady state drug concentration, the zero-order rate of release of a drug
p

from its dosage form is directly proportional to its rate of elimination.

• Thus drug with very short half-lives require faster rate of release, for a modest
duration of time while dosage form requires large dosage.

,.{-wln general, drugs with half-lives shorter than 2 hrs are poor candidates for sustained-
~ release preparations.

~Compounds with long half-lives, more than 8 hrs, are also generally not used in
~ sustaining forms, since there effect is already controlled.
/Margin of safety/therapeutic index

• Margin of safety of a drug can be described by considering therapeutic index. which

is the ration of median toxic dose and median effective dose.

Therapeutic index= TDso/EDso

• A drug is considered to be relatively safe with therapeutic index more than JO i.e.,
larger the ratio the more safuly...is.-the..drug_.__
th
• Margin of the safety of the drugs determined on the basis of therapeutic i11dex is c
nd
range of plasma concentration in which the drug is considered to th e safe a
therapeutically effective.

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1VM College of Pharmacy
...
 Dr. Mohd Azharuddin

• l'he drugs with narrow therapeutic indices the release pattern should be more precise
to maintain the plasma concentration within the narrow therapeutic and safety range.

• The unfavourable therapeutic index of a drug can be overcome by suitable

_/ employment of the CR mechanisms.

J Side effect

• The side effects of the some drugs are mainly developed due to fluctuation in the
plasma concentrations.

• The incidences of side effects can be minimized by controlling the concentration

within therapeutic range at any given time.

• The CR drug deliv~ry is the most widely used to incidences of the GI (local) s_ide
effects rather than a systemi~ side effect of the drug. -

• The drug properties which induce local or systemic side effect can be circumvented or
modified by their incorporation in a suitable oral CR delivery system that'employs a
specific controlled release mechanism .

~Disease state.
• Disease state and circadian rhythm are not drug properties, but they are equally
impo11ant as drug properties in considering a drug for CR.
I

For example:-

• Aspirin is a drug of choice for rheumatoid arthritis though it [Link] suitable for CR
dosage form.

• Still, aspirin CR dosage form could be advantageous to maintain therapeutic

concentrations, particularly throughout the night, thus alleviating morning stiffness.

• Asthma attacks are commonly occurring before bedtime, due to a low cortisol level.

• The highest cortisol level occurred between 12 midnight and 4 a.m.

• These variations entail for the design an oral CR delivery in accordance to circadian
rhythm.

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TVM College of Pharmacy